This project is a renewal application for the Stanford Genome Technology Center Grant. We propose developing three sets of enabling technologies and applications that offer the ability to query the complexity of the human genome and molecular aspects of human disease at a much reduced cost. These innovative technologies and approaches, given their enormous cost savings, make the application of genomics in clinical medicine a realistic proposition. With these novel tools, biomedical research will be improved, the scope of biological and clinical questions which can be addressed will be expanded and the resulting discoveries in human disease processes will accelerate the steady evolution of improvements in the way medicine is practiced. The first effort will develop sensitive, specific and rapid biosensors for querying minute amounts of samples that can be readily implemented in clinical settings. These technologies are fast - often real time. They are label-free and rely on nano-scale detection systems to provide significant improvements in sensitivity and cost. They have the potential to be implemented in the clinic. The second effort will focus on high-throughput technologies for the discovery of genomic factors that affect diseases. These are massively parallel technologies. They are more comprehensive than existing approaches, allow for the simultaneous interrogation of multiple aspects of the genome, improve our ability to make new discoveries of the molecular factors contributing to disease, provide huge cost savings and are useful for research using many patient samples. The third effort focuses on discovering the complex mix of genetic/genomic factors that are relevant to disease and therapeutics using the yeast model system. We know that, for the vast majority of diseases, multiple genetic factors contribute to the risk, severity and outcome of disease. Their interactions and the mechanisms by which they act are not readily understood today and our model organism approach and accompanying technologies allow these questions to be addressed. Taken together, the efforts proposed here are highly synergistic, leverage the strengths of the Center and develop new strengths in what we term "medical genomics" and molecular analysis for biomedical research. These efforts focus on having maximal impact on biomedical research and medicine.